Our AP4 center will focus on hereditary colorectal cancer (HCC) because: I) HCC, including Hereditary Non-polyposis Colon Cancer (HNPCC) and Familial Adenomatous Polyposis (FAP) are subsets (approximately 3%, approximately 1%) of colorectal cancer (CRC) and individuals carrying an HCC trait (a germline MMR or APC mutation) are at extremely high risk for CRC. 2) Our Director, Bruce Boman, MD, PhD, has great familiarity with basic and clinical HCC issues and is President of an HCC-dedicated organization of academic investigators - the Collaborative Group of the Americas for Inherited Colorectal Cancer (CGA-ICC). 3) Our team has an established track record of working with biotechnology and industry in cancer research. 4) Genetically defined subsets of CRC have tumors with different etiotogic mechanisms, patterns of mutations, biological behaviors and responses to treatments. The strategy of defining genetic subsets of CRC to develop more effective anti-cancer drugs is applicable to HNPCC and FAP carriers and patients because these are genetically well-defined cohorts. 5) Our team is poised to address pressing needs in the HCC field with promising research projects: P1- A need to identify all trait carriers before they develop CRC. Our solution is a serum-based immunoassay that quantifies wild type MMR or APC proteins in lymphocytes; P2/P3- A need for chemopreventives for trait carriers. We will develop, for FAP, mimetics of 15-LOX-1 & inhibitors of Beta-catenin/TCF-4/Survivin signaling. P4 - A need to detect HCC early, before advanced disease occurs. We will develop serum markers for early HCC detection. P5/P6 - A need for treatments for trait carriers with advanced disease. We will develop prototype new agents based on (a) the anti-proliferative effects of uroguanylin and (b) a GC-C Protein-based vaccine that elicits an immune response that attacks micrometastases but not the colon. The Center will also develop resources that promote collaborative, multidisciplinary HCC research projects among Center partners (e.g., database of HCC patients and researchers; tissue bank). Anticipated Outcomes of the planning year: i) identification of academic and industry partners and initial projects and establishment of collaborative, multidisciplinary working relationships among these partners; ii) planning and holding a successful Partners meeting (which will include discussions of the AP4 program, our Center research focus and administration, research projects, partner commitment and Center funding, intellectual property rights, strategic planning, 5 y application); iii) development of a detailed Strategic Plan; iv) financial and other commitments of partners; v) submission of an outstanding and fundable 5 y AP4 grant application.